In the present project we performed the two main studies to clarify the pathophysiology of endotoxin-induced lung injury using awake sheep with chronic lung lymph fistula. First study is to see the pathophysiology of TNF (tumor necrosis factor)-induced lung injury. After infusion of recombinant human TNF (r-hTNF) produced the almost same lung injuries as endotoxin-induced lung injury which we have reported^<1)>, such as the early pulmonary hypertension, transient leukopenia, decreased PaO_2 and the increased permeability pulmonary edema during the late phase. Pretreatment of selective thromboxane synthetase inhibitor, OKY-046, inhibited the early pulmonary hypertension induced by TNF, though other lung injuries did not change. Furthermore, the appearance of lung injuries induced by TNF occurred earlier 0.5-1hr than that induced by endotoxin. Secondly we examined the effects of recombinant human superoxide dismutase (r-hSOD) on endotoxin-induced lung injury to see the role of superoxide
… More anion (O_2^-). Treatment of r-h SOD suppressed lung injuries as mentioned above, but the degree of inhibition was approximately half.These results suggest that the mechanism of endotoxin-induced lung injury in awake sheep is complicated. O_2^- has an important role in this injury. However, we need to study the role of other oxygan radicals than O_2^- and some chemical mediators such as proteases. TNF infusion resulted in the same lung injury as that caused by endotoxin. Recently, intravascular macrophages (M*) are thought to have a central role in the development of endotoxin-induced lung injury. M* releases several mediators when stimulated by endotoxemia, and these mediators lead to lung injury. We need further studies to see whether TNF is crucial among these mediators.( ^<1)> Kubo and Kobayashi : Am Rev Respir Dis 132 : 494, 1985)3.今回の研究の問題点と今後の課題:今回の検討では、TNFが直接肺血管に作用した可能性があり、さらに検討を要する。また、活性酸素のみではETX肺損傷のすべてを説明することは困難であり、他の物質、特に好中球由来のエラスタ-ゼなどの関与も検討したい。最近ETX肺損傷の発生に肺血管内マクロファ-ジ(M¢)の関与が注目されている。ETXがM¢を活性化させ、種々の血管作動性物質を産生し傷害を惹起する、と考えられている。今後、M¢から放出される物質の検討が必要となる。また、従来より、ETX肺損傷の発生に好中球の関与が指摘されているが、好中球とM¢との関係にも注目したい。 Less